Antioxidants are commercially reported to slow the advance or severity of heart disease. As such, many patients of conventional health care are consuming antioxidant supplements from vitamins, minerals, and botanicals. However, little is understood of their potential mechanisms of action, confounding safety and efficacy evaluations. Botanicals represent a complex blend of phytochemicals, any of which may interact with prescribed drug regimens and alter their biological effects. In certain diseased states or medical interventions, these interactions could be deleterious to patient health and treatment. Heart disease commonly involves cardiac ischemia/reperfusion damage. Ischemia/reperfusion damage occurs when the heart is first denied then re-supplied with oxygen, generating damaging reactive oxygen species(ROS). Ischemia/reperfusion injury occurs across the span of heart disease - in a subtle, chronic fashion with congestive heart failure, or in an acute fashion as with cardiac surgical procedures. Ischemia/reperfusion damage is lowered through preconditioning, which occurs through brief periods of oxygen deprivation or through pretreatment with drugs such as opioids. Opioid pain-killers are used in emergent and surgical settings. One mechansism of opioid cardioprotection involves the generation of low levels of preconditioning ROS. Thus, ROS-quenching antioxidants may alter opioid cardioprotection. Synthetic antioxidants have been shown to experimentally decrease opioid cardioprotection, but no published studies have investigated the potential impact of dietary antioxidant supplementation. Our studies will utilize a standardized grape seed extract IH636, rich in antioxidant proanthocyanidins. Using rabbit cardiac myocyte and whole heart procedures, we will determine if three weeks of IH636 supplementation affects the expression of cardiac stress defense proteins or antioxidant reserve. We will also determine cardiac membrane integrity, cellular metabolism, heart function, and overall viability. In concert, we will evaluate cardiac effects of IH636 under ischemia/reperfusion conditions using the same endpoints. Finally, using knowledge of opioid mechansisms, our proposed studies will evaluate if IH636 supplementation interacts with opioid cardioprotection, and the nature of this interaction. For grape seed extract supplementation, both mechanisms of action and opioid interaction are currently unknown. Considering the increasing use of this botanical extract, improved knowledge of safety and efficacy is imperative.